The disclosure provides a novel process for the production of alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ester of Formula I, a precursor used for preparing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid of Formula II.

The acid of Formula II is used for produce fungicides. Annual productions of fungicides exceeds more than 30,000 metric tons. Any improvement in cost efficiency or waste reduction has large economic and environmental benefits.
The preparative routes for Formula I reported to date in the patent and non-patent literature all include reacting an alkyl haloethylacetate, such as an alkyl difluoroethylacetate of Formula III-A with alkyl acetate of Formula IV-A via Claisen ester condensation to provide the enolate salt of difluoroacetoacetate of Formula V-A.

The enolate salt of Formula V-A is then acidified to release the free alkyl difluoroacetoacetate of Formula VI-A.

The alkyl difluoroacetoacetate of Formula VI-A is then coupled with trialkyl orthoformate in the presence of excess acetic anhydride to provide an intermediate, alkyl 2-alkomethylene-4,4-difluoro-3-oxobutyrate of Formula VII.

The intermediate of Formula VII-A is then reacted with methylhydrazine hydrate to provide 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ester of Formula I-A, which can be hydrolyzed to give the acid of Formula II-A. Formula I-A is a particular form of generic Formula I in which R2 is CF2.

Much effort has been made to improve the reaction conditions and/or work up methods in order to achieve higher yields or greater purity and to reduce chemical waste.
Typically, the work up process of the Claisen condensation has included adding an acidic aqueous solution, such as HCl, HBr, H2SO4, H3PO4, or acetic acid aqueous solution to neutralize the basic salt of enolate of the ester. The released alkyl haloacetoacetate, typically difluoroacetoacetate, is used for next step after distillation.
WO 2009/106619 describes an improved method in which an acid, such as concentrated sulfuric acid, formic acid, acetic acid, oxalic acid, methanesulfonic acid or p-toluenesulfonic acid is added into the reaction mixture after the Claisen condensation in complete to acidify the basic enolate.
Alternatively, a gaseous acid, such as HCl-gas or HBr-gas is introduced into the reaction mixture accompanied by a small amount of water. The gas must be bubbled through the reaction mixture for several hours to release the free ester (Formula V, or more particularly Formula V-A or Formula V-B).
The resulting inorganic salt exists as a suspended solid, in the form of NaCl, NaBr, Na2SO4, sodium acetate, sodium methanesulfonate, or sodium formate, and is collected by filtration. The filtrate is used for next step.
The solid wastes produced in the existing procedures for producing a compound of Formula I are hazard and toxic. The accumulated amount from industrial production of Formula I can be up to ten thousand tons per year. Treating this amount of hazardous waste is a considerable manufacturing cost and inconvenience. Moreover, due to the corrosive nature of HCl-gas or HBr-gas the manufacturing facility must be corrosion resistant and must be fitted with corrosion resistant equipment.
WO 2011/113789 provided a minor additional improvement. After the Claisen condensation is completed without adding any water, excess HCl-gas is introduced. The HCl gas is bubbled through the reaction mixture for up to several hours. The formed inorganic solid is not removed. The whole suspended reaction mixture, including organic solvents and inorganic solids, is then transferred into another reactor for the next step. Transferring the viscous, crude reaction product is difficult.
Early literature and patents reported the pyrazole ring formation in a single solvent such as ethanol or water. The crude product required recrystallization for purification to provide light yellow solid, with a yield of about 60%.U.S. Pat. No. 7,863,460, U.S. Pat. No. 8,124,787, and JP 5232335 disclose similarly effective ring-closure methods. The methods are conducted in water and a water-immiscible organic solvent system in the presence of a base, which can produce a compound of Formula I with high regioselectivity for the desired isomer of Formula I, alkyl 5-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ester. Formula-VIII, the undesired isomer is produced as a minor component.

The base used for the ring closure reaction in the U.S. Pat. No. 7,863,460, U.S. Pat. No. 8,124,787, and JP 5232335 patents is selected from alkali metal hydroxides and alkali earth metal hydroxides. The amount of the base used is from 0.05 to 5.0 equivalents based on alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrate (Formula VII-A). When the ratio of base to compound of Formula VII-A reaches to 1:1 equivalents or higher the ester group has a tendency to be saponified to form the salt of Formula IX.
salt dissolves in the water phase and is taken off during two phase separation resulting in a loss of the product.
The above review of previously reported methods for preparing an alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ester of Formula I demonstrates the need for an improved reaction work-up following the Claisen condensation. and a method for producing an alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ester of Formula I without the use of strong acid to avoid the production of large amounts of hazardous waste and the difficulties of fitting a production facility for a corrosive manufacturing process. It is also desirable to provide a method for preparing a compound of Formula I in which the ring closure step is conducted with high yield and high regioselectivity.